1. Field of the Invention
The current disclosure is directed to pharmaceutical preparations, particularly pharmaceutical preparations for manufacturing transdermal patches.
2. Description of Related Art
“Drug-in-adhesive” transdermal systems contain a drug-containing adhesive polymer layer, a drug-impermeable backing layer overlying one side of the adhesive layer, and a release layer, such as a silicone-coated paper layer, overlying the other side of the adhesive layer. Generally, in “drug-in-adhesive” transdermal systems, the adhesive polymer forms an outer or continuous phase. Various pharmacologically inactive ingredients, such as fillers or plasticizers, may be dissolved or dispersed in the polymeric matrix. Suitable adhesive polymers may include hydrophobic polymers, such as polyisobutylenes or (meth)acrylate ester polymers. The adhesive polymers, together with fillers, plasticizers, and other pharmacologically inactive ingredients, make up an adhesive hydrophobic matrix.
The pharmacologically active ingredients can be either dissolved or dispersed in the hydrophobic matrix. The solubility and the physical properties of the active pharmaceutical ingredient are of great importance in influencing the physical as well as the drug delivery performance of the transdermal system.
Many active pharmaceutical ingredients are able to undergo changes in their physical form during processing, i.e., from one polymorph to another or from solid to liquid. Such changes in physical form can give rise to several issues during processing or manufacturing. These include issues of crystallization or re-crystallization. In some cases, exposure to high temperatures or pressures during processing can lead to changes in the physical form of the active pharmaceutical ingredient. For example, a crystalline drug with a low melting point may be added to an adhesive composition which is then subjected to further processing. The adhesive composition may be subjected to heat or pressure during an extrusion process to form an adhesive layer, causing the drug to melt. Upon cooling of the adhesive composition after extrusion, the drug may solidify in an amorphous form, or in a crystalline polymorphic form which is different from its original form. In other cases, the drug may form an oil which is dispersed through the adhesive matrix.
Such changes in the physical form of the drug can affect the transdermal system as a whole. For example, if the active pharmaceutical ingredient has a low melting point and converts from its solid state to an oil state during processing, the oil state of the active ingredient can plasticize the adhesive matrix. Plasticizing the adhesive matrix can in turn cause delamination of the adhesive matrix from the drug-impermeable backing or from the release layer. Also, plasticizing the adhesive matrix can cause “cold flow,” defined as distortion, deformation, or dimensional change at normal temperatures during storage conditions.
Additionally, if the active pharmaceutical ingredient is in oil form and is not sufficiently adsorbed in the adhesive matrix, or adsorbed by an excipient in the matrix, the oil can diffuse through the matrix and can cause film deposition or deposition of oil at the interface between the adhesive and the release liner interface. Diffusion of an oil through the adhesive matrix can also cause delamination and cold flow issues during storage.
Additionally, an adhesive layer may serve as a rate-limiting layer to control diffusion of oily drugs and other plasticizing agents from the drug reservoir to the interface between the reservoir and the backing.
There are known US marketed drug-in-adhesive transdermal products which contain a combination of polyisobutylene, mineral oil and colloidal silica as a transdermal matrix containing a drug such as scopolamine, clonidine or SALONPAS®. It has been claimed that the colloidal silica increases the viscosity in these products. It has also been claimed that the colloidal silica increases the permeability of the matrix, especially in transdermal products containing scopolamine or clonidine.
The present disclosure describes various embodiments, but is not intended to be exhaustive or limiting of the possible advantages that can be realized. Thus, the various embodiments are not intended to limit the scope of the invention. Accordingly, the present invention resides in the novel methods, arrangements, combinations, and improvements herein shown and described in various embodiments.